IL-3 and Oncogenic Abl Regulate the Myeloblast Transcriptome by Altering mRNA Stability
IL-3 and Oncogenic Abl Regulate the Myeloblast Transcriptome by Altering mRNA Stability
复制标题
DOI：
10.1371/journal.pone.0007469
复制
发表时间：
2009-10-15
期刊：
影响因子：
3.7
通讯作者：
Steinman, Richard A.
中科院分区：
文献类型：
--
作者：
Ernst, Jason;Ghanem, Louis;Steinman, Richard A.
生长因子白细胞介素-3（IL-3）促进多能造血祖细胞的存活和生长并刺激骨髓生成。据报道，它还可以通过自分泌或旁分泌机制对抗终末粒细胞生成并支持白血病细胞生长。IL-3在转录后水平发挥作用的程度在很大程度上是未知的。我们已经在32 Dcl 3成髓细胞中进行了全局mRNA衰变谱分析和生物信息学分析，表明IL-3在与成髓细胞功能相关的途径中引起了数百种转录物的立即早期稳定。稳定的转录物富含AU应答元件（战神），并且来自白细胞介素-6（IL-6）39-UTR的含ARE结构域使得异源基因对IL-3介导的转录物稳定化有应答。许多IL-3稳定的转录本与白血病转化有关。去调节的Abl激酶与IL-3共享延迟参与增殖或分化阻断的转录物的周转的能力，部分依赖于通过Mek/Erk途径的信号传导。这些发现支持IL-3通过mRNA稳定性控制作用的模型，并表明与IL-3连接的mRNA网络的异常稳定有助于白血病细胞生长。
The growth factor interleukin-3 (IL-3) promotes the survival and growth of multipotent hematopoietic progenitors and stimulates myelopoiesis. It has also been reported to oppose terminal granulopoiesis and to support leukemic cell growth through autocrine or paracrine mechanisms. The degree to which IL-3 acts at the posttranscriptional level is largely unknown. We have conducted global mRNA decay profiling and bioinformatic analyses in 32Dcl3 myeloblasts indicating that IL-3 caused immediate early stabilization of hundreds of transcripts in pathways relevant to myeloblast function. Stabilized transcripts were enriched for AU-Response elements (AREs), and an ARE-containing domain from the interleukin-6 (IL-6) 39-UTR rendered a heterologous gene responsive to IL-3-mediated transcript stabilization. Many IL-3-stabilized transcripts had been associated with leukemic transformation. Deregulated Abl kinase shared with IL-3 the ability to delay turnover of transcripts involved in proliferation or differentiation blockade, relying, in part, on signaling through the Mek/Erk pathway. These findings support a model of IL-3 action through mRNA stability control and suggest that aberrant stabilization of an mRNA network linked to IL-3 contributes to leukemic cell growth.